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Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance

dc.contributor.authorHuang, Jiansheng
dc.contributor.authorTao, Huan
dc.contributor.authorYancey, Patricia G.
dc.contributor.authorLeuthner, Zoe
dc.contributor.authorMay-Zhang, Linda S.
dc.contributor.authorJung, Ju-Yang
dc.contributor.authorZhang, Youmin
dc.contributor.authorDing, Lei
dc.contributor.authorAmarnath, Venkataraman
dc.contributor.authorLiu, Dianxin
dc.contributor.authorCollins, Sheila
dc.contributor.authorDavies, Sean S.
dc.contributor.authorLinton, MacRae F.
dc.date.accessioned2023-01-25T18:27:56Z
dc.date.available2023-01-25T18:27:56Z
dc.date.issued2023-01-13
dc.identifier.citationHuang J, Tao H, Yancey PG, Leuthner Z, May-Zhang LS, Jung JY, Zhang Y, Ding L, Amarnath V, Liu D, Collins S, Davies SS, Linton MF. Scavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance. Mol Metab. 2023 Jan;67:101651. doi: 10.1016/j.molmet.2022.101651. Epub 2022 Dec 5. PMID: 36481344; PMCID: PMC9792904.en_US
dc.identifier.issn2212-8778
dc.identifier.otherPubMed ID36481344
dc.identifier.urihttp://hdl.handle.net/1803/17947
dc.description.abstractObjective: Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr(-/-) mice. Methods: Male or female Ldlr(-/-) mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6C(hi) monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. Results: PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr(-/-) mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr(-/-) mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA-and IsoLG-lysyl adducts in Ldlr(-/-) mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr(-/-) mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1 beta expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6C(hi) monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr(-/-) mice. Conclusions: PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).en_US
dc.description.sponsorshipThis work was supported by National Institutes of Health Grants: HL116263, HL148137, and HL146134. Jiansheng Huang was supported by America Heart Association Postdoctoral Fellowship (19POST34450266). The analyses of urinary prostaglandin metabolites were performed in the Vanderbilt University Eicosanoid Core Laboratory.en_US
dc.language.isoen_USen_US
dc.publisherMolecular Metabolismen_US
dc.rightsÓ 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0).
dc.rightsOriginal content from this work may be used under the terms of the Creative Commons Attribution 4.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.
dc.source.urihttps://pubmed.ncbi.nlm.nih.gov/36481344/
dc.source.urihttps://www.webofscience.com/wos/woscc/full-record/WOS:000899822500001
dc.subjectCholesterol effluxen_US
dc.subjectHigh-density lipoprotein (HDL)en_US
dc.subjectMalondialdehyde (MDA)en_US
dc.subjectMacrophageen_US
dc.subjectMyeloperoxidase (MPO)en_US
dc.subject5'-O-Pentyl-pyridoxamine (PPM)en_US
dc.titleScavenging dicarbonyls with 5'-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistanceen_US
dc.typeArticleen_US
dc.identifier.doi10.1016/j.molmet.2022.101651
dc.identifier.doi10.3847/1538-3881/ac9f44


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